Ocular therapy using alpha-2 adrenergic receptor anterior compounds having enhanced clearance rates

ABSTRACT

Ophthalmically therapeutic materials, such as liquid-containing compositions and polymeric drug delivery systems, include a therapeutic component which includes an alpha 2 adrenergic receptor agonist that is cleared from the anterior segment of an individual&#39;s eye to which the material is administered. The alpha 2 adrenergic receptor agonist may have a vitreal half-life greater than about three hours. The present materials are effective in treating an ocular condition(s) that affect the anterior segment of an eye, or the anterior and posterior segment of the eye. The materials are suitable for intravitreal or periocular administration and can provide prolonged drug delivery and therapeutic benefits to patients to which the materials have been administered. The alpha 2 adrenergic receptor agonists can be provided in liquid-containing formulations and/or bioerodible and/or non-bioerodible polymeric implants and microparticles. Methods of making and using the present materials are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Application No.60/679,771, filed May 10, 2004, the content of which in its entirety ishereby incorporated by reference.

BACKGROUND

The present invention generally relates to the use of alpha-2 adrenergicreceptor agents that are cleared from the anterior of an eye to treat aneye of a patient, and more specifically to ophthalmic compositions anddrug delivery systems that provide extended release of the alpha-2adrenergic receptor agents to an eye to which the agents areadministered; and to methods of making and using such compositions andsystems, for example, to treat or reduce one or more symptoms of anocular condition to improve or maintain vision of a patient.

In ocular therapies, alpha agonists (e.g., agonists of alpha adrenergicreceptors) are used to reduce aqueous humor production and increaseaqueous humor outflow through the trabecular meshwork. The outflowthrough the trabecular meshwork accounts for about 90% of the eye'sfluid drainage capability, and the remaining approximately 10% isprovided by the uveoscleral outflow where fluid flows into the ciliarmuscle beneath the trabecular meshwork. Two examples of alpha agonistsused for ocular therapy include apraclonidine (IOPIDINE) andbrimonidine-P (ALPHAGAN-P).

Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline, is analpha-2-selective adrenergic receptor agonist that is effective in thetreatment of open-angle glaucoma by decreasing aqueous humor productionand increasing uveoscleral outflow. Apraclonidine generally has a mixedalpha-1 and alpha-2 stimulatory activity. Brimonidine is available intwo chemical forms, brimonidine tartrate and brimonidine free base.Brimonidine tartrate (Alphagan® P) is publicly available by Allergan fortreating glaucoma. Topical ocular brimonidine formulation, 0.15%Alphagan® P (Allergan, Irvine, Calif.), is currently commerciallyavailable for treatment of open-angle glaucoma. The solubility ofbrimonidine tartrate in water is, 34 mg/mL in water and 2.4 mg/mL in apH 7.0 phosphate buffer while the solubility of brimonidine freebase isnegligible in water.

Recent studies have suggested that brimonidine can promote survival ofinjured retinal ganglion nerve cells by activation of thealpha-2-adrenoceptor in the retina and/or optic nerve. For example,brimonidine can protect injured neurons from further damage in severalmodels of ischemia and glaucoma.

Glaucoma-induced ganglion cell degeneration is one of the leading causesof blindness. This indicates that brimonidine can be utilized in a newtherapeutic approach to glaucoma management in which neuroprotection andintraocular pressure reduction are valued outcomes of the therapeuticregimen. For brimonidine to protect the optic nerve, however, it musthave access to the posterior segment of the eye at therapeutic levels.Currently available techniques for administering brimonidine to theposterior chamber of the eye are not sufficient to address this issue.

Agents that are administered to the vitreous of an eye of a patient canbe eliminated from the vitreous by diffusion to the retro-zonular space(anterior clearance) with clearance via the aqueous humor, such asthrough the trabecular meshwork outflow and the uveoscleral outflow, orby trans-retinal elimination (posterior clearance). Most compounds thatare relatively hydrophilic to moderately lipophilic utilize the former(anterior clearance) pathway unless a facilitated or active transportmechanism exists for these while extremely lipophilic compounds andthose with trans-retinal transport mechanisms will utilize the latter(i.e., will go out through the retina). For example, macromolecules andpeptides, including antibiotics, are often eliminated via the anteriorroute. In comparison, existing alpha 2 adrenergic receptor agonists areeliminated via the posterior route. This is most likely the result of anorganic cationic transport mechanism in the outer blood retinal barrier,the RPE. Unfortunately, compounds that are eliminated across the retinahave extremely short intravitreal half-lives. Additionally, thesecompounds tend to have extremely small aqueous humor/vitreous humorconcentration ratios at steady-state. This dramatically impacts thetreatment of anterior tissues from posterior administration of suchcompounds.

Intravitreal delivery of therapeutic agents can be achieved by injectinga liquid-containing composition into the vitreous, or by placingpolymeric drug delivery systems, such as implants and microparticles,into the vitreous. Examples of biocompatible implants for placement inthe eye have been disclosed in a number of patents, such as U.S. Pat.Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856;5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and6,699,493.

Other ocular therapies may include periocular delivery of drugs to apatient. Penetration of drugs directly into the posterior segment of theeye is restricted by the blood-retinal barriers. The blood-retinalbarrier is anatomically separated into inner and outer blood barriers.Movement of solutes or drugs into the internal ocular structures fromthe periocular space is restricted by the retinal pigment epithelium(RPE), the outer blood-retinal barrier. The cells of this structure arejoined by zonulae oclludentae intercellular junctions. The RPE is atight ion transporting barrier that restricts paracellular transport ofsolutes across the RPE. The permeability of most compounds across theblood-retinal barriers is very low. Extremely lipophilic compounds,however, such as chloramphenical and benzyl penicillin, can penetratethe blood-retinal barrier achieving appreciable concentrations in thevitreous humor after systemic administration. The lipophilicity of thecompound correlates with its rate of penetration and is consistent withpassive cellular diffusion. The blood retinal barrier, however, isimpermeable to polar or charged compounds in the absence of a transportmechanism. Hydrophilic to moderately lipophilic drugs can diffuse intothe iris-ciliary body achieving very low posterior chamber or iris rootconcentrations. Anterior bulk flow of aqueous humor competes with theposterior elimination of drugs. For compounds that cannot passivelypenetrate the RPE, but are eliminated across the retina, it isextraordinarily difficult to achieve therapeutic concentrations of drugsat reasonable doses due to the differential rate processes involved.

Thus, there remains a need for new agents that can be used to treatocular conditions, and that have different pharmacokinetic propertiesthan existing agents.

SUMMARY

Ophthalmically therapeutic materials, such as liquid-containingcompositions and polymeric drug delivery systems, include a therapeuticcomponent which includes an alpha 2 adrenergic receptor agonist that iscleared from the anterior segment of an individual's eye to which thematerial is administered. The alpha 2 adrenergic receptor agonist mayhave a vitreal half-life greater than about three hours. The presentmaterials are effective in treating an ocular condition(s) that affectthe anterior segment of an eye, or the anterior and posterior segment ofthe eye. The materials are suitable for intravitreal or periocularadministration and can provide prolonged drug delivery and therapeuticbenefits to patients to which the materials have been administered. Thealpha 2 adrenergic receptor agonists can be provided inliquid-containing formulations and/or bioerodible and/or non-bioerodiblepolymeric implants and microparticles. Methods of making and using thepresent materials are also described.

Ophthalmically therapeutic materials in accordance with the disclosureherein comprise a therapeutic component that comprises a therapeuticallyeffective amount of an alpha 2 adrenergic receptor agonist having astructure effective in providing elimination of the agonist from theanterior chamber of an eye to which the agonist is administered.

The anteriorly cleared alpha-2 adrenergic receptor agonists of thepresent materials may be an agonist or agent that selectively activatesalpha-2 adrenergic receptors, for example by binding to an alpha-2adrenergic receptor, relative to other types of adrenergic receptors,such as alpha-1 adrenergic receptors. The selective activation can beachieved under different conditions, but preferably, the selectiveactivation is determined under physiological conditions, such asconditions associated with an eye of a human or animal patient.

A method of producing the present ophthalmically therapeutic materialsmay comprise selecting an alpha 2 adrenergic receptor agonist that has avitreous half-life greater than about 3 hours; and combining theselected alpha 2 adrenergic receptor agonist with a liquid carriercomponent or a polymeric component to form a material suitable foradministration to an eye.

Methods of treating one or more ocular conditions comprise a step ofadministering the present materials to an eye of a patient. Thematerials can be intravitreally administered and/or periocularlyadministered. When drug delivery systems are used to deliver theanteriorly cleared alpha 2 adrenergic receptor agonists, sustaineddelivery and prolonged therapeutic benefits can be obtained.

Kits in accordance with the present invention may comprise one or moreof the present materials, and instructions for using the materials. Forexample, the instructions may explain how to administer the materials toa patient, and types of conditions that may be treated with thematerials.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent. In addition, any feature orcombination of features may be specifically excluded from any embodimentof the present invention.

Additional aspects and advantages of the present invention are set forthin the following description, examples, and claims, particularly whenconsidered in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the vitreal concentration of brimonidine as afunction of time after a single intravitreal administration of 928 ng ofbrimonidine into the vitreous of rabbit eyes (n=4).

DESCRIPTION

Ophthalmically therapeutic materials and methods have been inventedwhich provide effective treatment of ocular conditions, such asdisorders or diseases of the anterior and/or posterior segment of an eyeof an individual, such as a human or animal. The present ophthalmicallytherapeutic materials comprise a therapeutic component which comprisesan alpha 2 adrenergic receptor agonist. The alpha 2 adrenergic receptoragonists of the present materials have structures that are effective inproviding anterior clearance or elimination of the agonist from the eye.For example, the alpha 2 adrenergic receptor agonists of the presentmaterials have structures that are effective in permitting the agoniststo be cleared via the anterior route or the anterior chamber, ascompared to the posterior route or via the retina of an eye to which thematerials are administered. Thus, the present materials can provide oneor more therapeutic effects for treating anterior ocular conditions,posterior ocular conditions, and combinations of anterior and posteriorocular conditions. For example, the present materials can reduceelevated intraocular pressure in an eye, can provide neuroprotection,and treat glaucoma, and/or can reduce intraocular pressure and provideneuroprotection.

DEFINITIONS

For the purposes of this description, we use the following terms asdefined in this section, unless the context of the word indicates adifferent meaning.

As used herein, an “intraocular drug delivery system” refers to a deviceor element that is structured, sized, or otherwise configured to beplaced in an eye. The present drug delivery systems are generallybiocompatible with physiological conditions of an eye and do not causeunacceptable or undesirable adverse side effects. The present drugdelivery systems may be placed in an eye without disrupting vision ofthe eye. The present drug delivery systems may be in the form of aplurality of particles, such as microparticles, or may be in the form ofimplants, which are larger in size than the present particles.Intraocular drug delivery systems described herein include a polymericcomponent.

As used herein, a “composition” refers to a material suitable foradministration to an eye of an individual. Compositions may include apolymeric drug delivery systems if desired. Compositions may comprise aliquid carrier, and compositions refers to material such as solutions,suspensions, emulsions, and the like.

As used herein, a “therapeutic component” refers to a portion of a drugdelivery system or composition comprising one or more therapeuticagents, active ingredients, or substances used to treat a medicalcondition of the eye. The therapeutic component may be a discrete regionof an intraocular implant, or it may be homogenously distributedthroughout the implant or particles or composition. The therapeuticagents of the therapeutic component are typically ophthalmicallyacceptable, and are provided in a form that does not cause adversereactions when the ophthalmically therapeutic material is placed in aneye.

As used herein, “associated with” means mixed with, dispersed within,coupled to, covalently bonded, covering, or surrounding.

As used herein, an “ocular region” or “ocular site” refers generally toany area of the eyeball, including the anterior and posterior segment ofthe eye, and which generally includes, but is not limited to, anyfunctional (e.g., for vision) or structural tissues found in theeyeball, or tissues or cellular layers that partly or completely linethe interior or exterior of the eyeball. Specific examples of areas ofthe eyeball in an ocular region include the anterior chamber, theposterior chamber, the vitreous cavity, the choroid, the suprachoroidalspace, the subretinal space, the conjunctiva, the subconjunctival space,the episcleral space, the intracorneal space, the epicorneal space, thesclera, the pars plana, surgically-induced avascular regions, themacula, and the retina.

As used herein, an “ocular condition” is a disease, ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. Broadly speaking the eye includes the eyeball and the tissues andfluids which constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the iris but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,retinal pigmented epithelium, Bruch's membrane, optic nerve (i.e. theoptic disc), and blood vessels and nerves which vascularize or innervatea posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic opthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

The term “biodegradable polymer” refers to a polymer or polymers whichdegrade in vivo, and wherein erosion of the polymer or polymers overtime occurs concurrent with or subsequent to release of the therapeuticagent. The terms “biodegradable” and “bioerodible” are equivalent andare used interchangeably herein. A biodegradable polymer may be ahomopolymer, a copolymer, or a polymer comprising more than twodifferent polymeric units.

The term “treat”, “treating”, or “treatment” as used herein, refers toreduction or resolution or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of agent needed to treat an ocular condition, orreduce or prevent ocular injury or damage without causing significantnegative or adverse side effects to the eye or a region of the eye.

The present materials described herein include, without limitation,liquid-containing compositions, such as formulations, and polymeric drugdelivery systems. The present compositions may be understood to includesolutions, suspensions, emulsions, and the like, such as otherliquid-containing compositions used in ophthalmic therapies. Polymericdrug delivery systems comprise a polymeric component, and may beunderstood to include biodegradable implants, nonbiodegradable implants,biodegradable microparticles, such as biodegradable microspheres, andthe like. The present drug delivery systems may also be understood toencompass elements in the form of tablets, wafers, rods, sheets, and thelike. The polymeric drug delivery systems may be solid, semisolid, orviscoelastic.

The agonists of the present materials refer to agents that bind orinteract with a target receptor, such as a receptor expressed on a cellsurface, and activate that target receptor. As used herein, the alpha 2adrenergic receptor agonist is an agent that selectively interacts withalpha 2 adrenergic receptors. For example, an alpha 2 adrenergicreceptor agonist of the present material is typically an agent thatselectively activates alpha-2 adrenergic receptors relative to alpha-1adrenergic receptors. In certain materials, the alpha-2 adrenergicreceptor agonist selectively activates or stimulates a subtype of thealpha-2 adrenergic receptors. For example, the agonist may selectivelyactivate one or more of the alpha-2a, the alpha-2b, or the alpha-2creceptors, under certain conditions, such as physiological conditions.The present agonists may partially activate or fully activate alpha 2adrenergic receptors. The present agonists may also be understood toencompass modified or engineered alpha 2 adrenergic receptor agonists,such as a conventional or publicly known alpha 2 adrenergic receptoragonist that has been modified or engineered to have the desiredanterior clearance described herein. Modified or engineered alpha 2adrenergic receptor agonists interact with alpha 2 adrenergic receptorsto activate the receptors, but differ from other alpha 2 adrenergicreceptor agonists at least by the clearance of such agonists from theeye. For purposes of convenience, the alpha 2 adrenergic receptoragonists of the present materials may also be referred to as “anteriorlycleared alpha 2 adrenergic receptor agonists”.

Certain embodiments of the present materials comprise a therapeuticcomponent that comprises an alpha 2 adrenergic receptor agonist that ispreferentially cleared via the anterior segment of an eye relative tothe posterior segment of the eye. Or, stated differently, the alpha 2adrenergic receptor agonist is cleared from the eye by mixing with theaqueous humor present in the anterior and/or posterior chambers of aneye or through the iris-ciliary body, as opposed to being cleared viathe retina of the eye. In certain embodiments, the alpha 2 adrenergicreceptor agonist has an anterior clearance rate that is at least 30%greater than a posterior clearance rate. For example, the alpha 2adrenergic receptor agonist may have an anterior clearance rate that isat least about 40% greater, or 50% greater, or 60% greater, or 70%greater, or 90% greater than the posterior clearance rate. Thus thealpha 2 adrenergic receptor agonists have a greater anterior clearancerate/posterior clearance rate ratio than other alpha 2 adrenergicreceptor agonists that are cleared via the retina. In addition, thealpha 2 adrenergic receptor agonists may have a high aqueoushumor/vitreous humor concentration ratio. The enhanced anteriorclearance can be observed when the alpha 2 adrenergic receptor agonistis administered intraocularly, such as into the posterior segment of aneye, such as into the vitreous of an eye, and can be observed when thealpha 2 adrenergic receptor agonist is administered periocularly, suchas when the agent is administered into one or more of the followingregions: retrobulbar regions, subconjunctival regions, subtenon regions,suprachoroidal regions, and intrascleral regions. In many situations,the alpha 2 adrenergic receptor agonist will be cleared from the eye bypassing from the anterior chamber through the trabecular meshwork at theangle or the filtration angle.

In other embodiments, the alpha 2 adrenergic receptor agonist has asubstantially equal anterior and posterior clearance rate. Importantly,the present materials comprise an alpha 2 adrenergic receptor agonistthat has a measurable anterior clearance. For example, when administeredto the vitreous of an eye, a sample of the aqueous humor obtained froman individual will contain a measurable amount of the alpha 2 adrenergicreceptor agonist after a certain time period. In comparison, existingalpha 2 adrenergic receptor agonists, such as brimonidine, are notdetected or are not calculable in the aqueous humor when administeredintravitreally or periocularly, as discussed herein.

As discussed above, the therapeutic component of the present materialsmay comprise a modified or engineered alpha-2 adrenergic agonist. Forexample, the modified or engineered alpha-2 adrenergic agonist maycomprise a base structure effective in interacting with or activating analpha-2 adrenergic receptor, and a bulking agent or modifier componentassociated with the base structure to provide an enhanced anteriorclearance relative to an identical base structure without the bulkingagent or modifier component. The bulking agent or modifier component maybe coupled to or covalently bonded with the base structure. For example,the bulking agent or modifier component may be directly covalentlybonded to the base structure, or it may be indirectly coupled to thebase structure via one or more linking agents. The bulking agent ormodifier component can alter the hydrophilicity or lipophilicity of thebase structure to achieve the desired anterior clearance. Preferably,the bulking agent or modifier component does not substantially interferewith the base structure's interaction with an alpha-2 adrenergicreceptor.

Some modified or engineered alpha-2 adrenergic receptor agonists maycomprise a bulking agent or modifier component associated with the basestructure in a manner which permits the bulking agent or modifiercomponent to disassociate from the base structure under certainconditions. For example, a bulking agent may be temporarily bonded withthe base structure, and after a certain amount of time, the bonddegrades and the base structure is released from the bulking agent. Thebond may be sensitive to light passing through the eye, or it may besensitive to one or more chemical agents that can be topically appliedto the eye. Or, the base structure may be complexed with the bulkingagent or modifier component, and the complex dissociates over time inthe vitreous of an eye.

One non-limiting example of a modified or engineered alpha-2 adrenergicreceptor agonist that has a relatively long vitreal half-life is analpha-2 adrenergic receptor agonist coupled to a polyethylene glycol(PEG). For example, a PEG agent may be covalently bonded to an amino orsulfhydryl group present on the alpha-2 adrenergic receptor agonist viaa chemically reactive group on the PEG agent. The resulting modified orengineered alpha-2 adrenergic receptor agonist can be linear or branchedin structure. In certain embodiments, the PEG agent has a molecularweight from about 30 kDa to about 60 kDa, for example about 40 kDa orabout 50 kDa.

A second non-limiting example of a modified or engineered alpha-2adrenergic receptor agonist that has a relatively long vitreal half-lifeis an alpha-2 adrenergic receptor agonist that includes one or morelipophilic components. For example, the alpha-2 adrenergic receptoragonist may be coupled to a hydrophobic hydrocarbon including one ormore hydrophilic groups. One example of such an agent includeshydroxy-containing hydrocarbons. Such agents can be effective to provideboth hydrophobic and hydrophilic groups and thereby alter thevitreal-half life of the alpha-2 adrenergic agonist. One specificexample of a modified or engineered alpha-2 adrenergic receptor agonistincludes alkylpropanediol coupled to an alpha-2 adrenergic receptoragonist. Additional examples include alkylpropanediols other than1-O-hexadecylpropanediol. 1-O-hexadecylpropanediol has been shown to beeffective in slowing the release of ganciclovir into the vitreous ofrabbit eyes (Cheng et al., “Treatment or prevention of herpes simplexvirus retinitis with intravitreally injectable crystalline1-O-Hexadecylpropanediol-3-phospho-ganciclovir”, (2002) InvestigativeOpthalmology & Visual Science, 43(2):515-521).

Additional examples of suitable bulking agents or modifier componentscan be identified and obtained using routine methods known to persons ofordinary skill in the art. Thus, the alpha 2 adrenergic receptoragonists of the present therapeutic components can be identified byscreening the agents for the desired pharmacokinetic properties, such asvitreal half-life, aqueous humor/vitreous humor concentration ratios,and the like, using the methods described above. The screened orselected alpha 2 adrenergic receptor agonists can then be combined withone or more components or component precursors of the presentcompositions and drug delivery systems.

The bulking agent or modifier component may be effective in increasingthe molecular weight of the alpha 2 adrenergic receptor agonists. Withthe increased molecular weight, the alpha 2 adrenergic receptor agonistsmay exhibit a reduced posterior clearance rate from an eye, and/or mayexhibit an enhanced anterior clearance from the eye. One example of amodified alpha 2 adrenergic receptor agonist includes a brimonidine basestructure coupled or associated with a polyethylene glycol. The alpha-2adrenergic agonist of the therapeutic component may have a greateraqueous humor/vitreous humor concentration ratio and greater vitrealhalf-life relative to other alpha-2 adrenergic receptor agonists, suchas brimonidine.

Another example of a modified or engineered alpha-2 adrenergic receptoragonist that has a relatively long vitreal half-life is an alpha-2adrenergic receptor agonist that prevents trans RPE transport by theorganic cation transporters. At physiologic pH many of the alpha 2adrenergic receptor agonists are positively charged. Transport oforganic cations can be mediated by substrate-specific, sodium-dependenttransporters and by less specific sodium-independent transporters. Twomajor families of organic cation transporters have been identified:organic cation transporters (OCT) and organic cation/carnitinetransporters (OCTN). The OCT transporters have been identified in theretinal pigmented epithelium (the outer blood-retinal barrier).Additionally, a novel organic cation transporter, distinct from theknown OCT family, has been identified in the RPE.

Brimonidine is a substrate for the organic cation transporter present inthe conjunctiva. It is possible that elimination of brimonidine acrossthe retina/RPE may be a result of an organic cation transporter. The pKaof the imidazole nitrogen on brimonidine is 7.78.

Thus, the present alpha 2 adrenergic receptor agonists may be effectiveagents in activating alpha 2 adrenergic receptors without being asubstrate for organic cation transporters. Such agonists may notnecessarily include a bulking agent, as described above. For example,generating an N-Mannich base prodrug may create a compound that is not asubstrate for the organic cation transporters. Another example of thepresent alpha-2 adrenergic receptor agonists that could possess adecreased organic cation transport is a sulfonyl prodrug of brimonidine.These compounds would be expected to have a decreased transretinalelimination and prolonged vitreous half-life. Synthesis of thesecompounds is straight forward by those skilled in the art.

Thus, certain embodiments of the present alpha 2 adrenergic receptoragonists may be non-cationic at a physiological pH, such as at the pH ofthe interior of an eye. In other words, the present agonists can bepresent as neutrally charged or anionic molecules in the interior of aneye. In certain embodiments, the present agonists are non-cationic at apH from about 6.0 to about 7.8. For example, the present agonists arenon-cationic at a pH from about 7.0 to about 7.4. In certainembodiments, the agonists are non-cationic at a pH of about 7.2, or at apH of about 7.3, or at a pH of about 7.4. In certain embodiments, amajor portion of the present agonists in the compositions and/or drugdelivery systems are non-cationic at the recited pHs or pH ranges. Forexample, about 90%, or about 80%, or about 70%, or about 60%, or about50% of the agonists may be non-cationic at the recited pHs or pH ranges.

When the present alpha 2 adrenergic receptor agonists are organiccations (e.g., organic molecules having a transient or permanentpositive net charge), the agonists may have a basic functionality with apKa of less than about 7. Certain agonists may have a pKa of about 6.5,or about 6, or about 5.5, or about 5.

Additional alpha 2 adrenergic receptor agonists in accordance with thepresent disclosure include alpha 2 adrenergic receptor agonists thathave no ionizable groups. Other additional alpha 2 adrenergic receptoragonists may have only acidic functionalities, as compared to basicfunctionalities. Acidic functionalities may be provided by coupling orassociating one or more acidic moieties with an alpha 2 adrenergicreceptor agonist base structure.

One example of an N-Mannich base prodrug is provided below as compoundA.

This N-Mannich base prodrug will have a pKa of 6.9, thus having a muchhigher fraction of uncharged species. Chemical decomposition back tobrimonidine can occur. Optimizing the rate of decomposition back tobrimonidine may result in an appropriate vitreous half-life.

An example of a sulfonyl prodrug is provided below as compound B:

The rate of chemical hydrolysis of the sulfonyl prodrugs back tobrimonidine can be optimized by judicious selection of sulfonyl moiety.The sulfonyl prodrug will have a pKa of 5 and will be uncharged atphysiologic pH.

Another example of the present alpha 2 adrenergic receptor agonistsinclude agents that activate alpha 2 adrenergic receptors and that areneutral at a physiological pH. For example, the alpha 2 adrenergicreceptor agonist is not a cation at a physiological pH, such as at thepH of the interior of an eye of a human. One example of such an agonistis provided below as compound C.

Another example of such an alpha 2 adrenergic receptor agonist isprovided below as compound D

Another example of such an alpha 2 adrenergic receptor agonist isprovided below as compound E

Anteriorly cleared alpha 2 adrenergic receptor agonists can beidentified and obtained using standard pharmacokinetic experiments andconventional methods that are routine to persons of ordinary skill inthe art. For example, potential anteriorly cleared alpha 2 adrenergicreceptor agonists can be produced using conventional chemical synthesistechniques, such as techniques suitable for producing conventional alpha2 adrenergic receptor agonists, such as brimonidine, xylazine,medetomidine, ketamine, clonidine, apraclonidine, and the like. Ifdesired, the alpha 2 adrenergic receptor agonist can be modified orengineered, as described above. The alpha 2 adrenergic receptor agonistactivity can be examined using conventional screening assays for testingconventional alpha 2 adrenergic receptor agonists. Such screening assaysare routine to persons of ordinary skill in the art.

Potential anteriorly cleared alpha 2 adrenergic receptor agonists can bescreened by injecting the potential agonist into a rabbit vitreous. Thevitreous humor and aqueous humor can be sampled as a function of time,and the amount of the potential agonist in the vitreous and aqueoushumor can be measured. The vitreous concentration of the potentialagonist can be plotted as a function of time, and using standardpharmacokinetic techniques, the vitreous half-life for the potentialagonist and clearance of the potential agonist can be calculated.Similarly, the aqueous concentration of the potential agonist can beplotted as a function of time, and standard pharmacokinetic techniquescan be used to determine the anterior clearance of the potentialagonists. Agents with desired vitreal half-lives and/or that aremeasurable in the aqueous humor may be used in the present materials.For example, agents that have vitreous half-lives greater than aboutthree hours can be selected for the present ophthalmically therapeuticmaterials.

Compounds that have a short vitreal half-life (e.g., less than aboutthree hours), are likely eliminated from the eye via a posterior routeacross the retina (Cunha-Vaz et al., “The active transport offluoroscein by the retinal vessels and the retina”, J. Physiol.,191:467-486 (1967); Barza et al., “The effects of infection andprobenecid on the transport of carbenicillin from the rabbit vitreoushumor”, Invest Opthalmol Vis. Sci., 22:720-726 (1982); Miller et al.,“Fleroxacin pharmacokinetics in aqueous and vitreous humorsdetermination by using complete concentration-time data from individualrabbits”, Antimicrob. Agents. Chemother., 36:32-38 (1992); Cunha-Vaz,“The blood-ocular barriers”, Surv. Opthalmol., 5:279-296 (1979); Mauriceet al., “Handbook of Experimental Pharmacology: Pharmacology of theEye”, Sears, Eds., Vol. 69, (Springer-Verlag, Berlin-Heidelberg), 19-116(1986); and Lesar et al., “Antimicrobial drug delivery to the eye”, DrugIntell Clin. Pharm., 19:642-654 (1985)).

Because of the large surface are of the retina available for exchangesbetween the vitreous and plasma, strict anterior diffusion of moleculesdoes not occur for compounds able to cross the retina and the retinalpigment epithelium (RPE). Instead, the compounds will radially diffusefrom an initial concentration distribution followed by elimination fromthe vitreous across the retina (e.g., the trans-retinal or posteriorelimination route). Additionally, a low aqueous humor/vitreous humorconcentration ratio for the compound is further evidence of atrans-retinal mechanism of elimination for such compounds (Maurice, “Theexchange of sodium between the vitreous body and the blood and aqueoushumor”, J. Physiol, 137:119-125 (1957); and Maurice, “Protein dynamicsin the eye studied with labelled proteins”, Am J Opthalmol, 49:361-367(1959)).

In comparison, compounds eliminated by the anterior chamber route willdevelop an aqueous humor/vitreous humor concentration ratio thatcorrelates well with their molecular weight (Maurice et al., “Handbookof Experimental Pharmacology: Pharmacology of the Eye”, Sears, Eds.,Vol. 69, (Springer-Verlag, Berlin-Heidelberg), 19-116 (1986)). Examplesof compounds that are cleared by the anterior route include albumin,gentamicin, streptomycin, sulfacetamide tobramycin, kanamycin, as wellas other macromolecules and peptides. It is important to note that suchcompounds are not alpha 2 adrenergic receptor compounds.

In view of the above, one embodiment of the present invention, relatesto an ophthalmically therapeutic material that comprises a therapeuticcomponent which comprises a therapeutically effective amount of an alpha2 adrenergic receptor agonist having a structure effective in providingelimination of the agonist from the anterior chamber of an eye to whichthe agonist is administered. For example, the ophthalmically therapeuticmaterial comprises an alpha 2 adrenergic receptor agonist that iscleared via the anterior route (e.g., through the trabecular meshworkoutflow and/or the uveoscleral outflow) compared to being cleared solelythrough the posterior route (e.g., through the retina).

The alpha 2 adrenergic receptor agonist of the present materials isprovided in an amount effective in providing one or more therapeuticeffects. For example, a material may comprise an amount of an anteriorlycleared alpha 2 adrenergic receptor agonist that providesneuroprotection to the neurons in an eye, a reduction in elevatedintraocular pressure, and combinations thereof. As another example, theanteriorly cleared alpha 2 adrenergic receptor agonists may be providedin amounts that are effective in treating glaucoma. In certainmaterials, such as the polymeric drug delivery systems described herein,the anteriorly cleared alpha 2 adrenergic receptor agonist may bereleased from the drug delivery system in such therapeutically effectiveamounts.

Some of the present materials comprise an alpha 2 adrenergic receptoragonist that has an intravitreal half-life after solution dosing greaterthan about three hours. For example, certain materials comprises ananteriorly cleared alpha 2 adrenergic receptor agonist that has anintravitreal half life of 4 hours, or 5 hours, or 10 hours, or 15 hours,or more. Half-life determination of such agonists can be determined asdescribed herein.

The alpha 2 adrenergic receptor agonist of the present materials may beassociated with a bulking agent, as described herein. For example, analpha 2 adrenergic receptor agonist may be coupled to a polyethyleneglycol (PEG). In certain embodiments, the alpha 2 adrenergic receptoragonist has a molecular weight greater than the molecular weight of adifferent alpha 2 adrenergic receptor agonist that is eliminated fromthe posterior segment of an eye (e.g., via the trans-retinal route).

As discussed herein, the alpha 2 adrenergic receptor agonists of thepresent materials may have substantially equal anterior and posteriorclearance rates, or may have an enhanced anterior clearance raterelative to the posterior clearance rate. In some materials, theanterior clearance rate is less than the posterior clearance rate, butthe alpha 2 adrenergic receptor agonist has an anterior clearance ratethat is effective in permitting the alpha 2 adrenergic receptor agonistto be measured above a quantitation limit in the aqueous humor of an eyeto which it has been administered.

The present materials are ophthalmically acceptable. Thus, the presentmaterials can be administered to an eye of an individual withoutsubstantial negative or adverse side effects. In certain materials, thealpha 2 adrenergic receptor agonist is delivered to the anteriorchamber, the posterior chamber, or a combination of the anterior chamberand posterior chamber when the material is administered to the eye.

As discussed herein, the present materials can be produced by a varietyof methods. In one embodiment, the ophthalmically therapeutic materialcomprises a therapeutic component produced by a process comprising astep of selecting an alpha 2 adrenergic receptor agonist that has avitreous half-life greater than about three hours. Methods ofdetermining the vitreous half-life of such agonists are describedherein. Other embodiments may comprise selecting an agonist that has avitreous half-life of about 4 hours, or 5 hours, or 10 hours, or 15hours, or more.

In certain embodiments, the present materials comprise a therapeuticcomponent produced by a process comprising administering an alpha-2adrenergic receptor agonist to an eye of a subject; determining theconcentration of the alpha-2 adrenergic receptor agonist in the vitreousbody or vitreous humor and/or aqueous humor as a function of time;determining the vitreous half-life and/or clearance of the alpha-2adrenergic receptor agonist; and combining the alpha-2 adrenergicreceptor agonist with at least one other component useful in the presentmaterials if the half-life of the alpha-2 adrenergic receptor agonist isgreater than about three hours. In situations where modeling methods maybe used, some of the foregoing steps used to produce the therapeuticcomponent may be changed or omitted. Thus, the therapeutic component maybe produced by a process comprising determining whether the half-life ofthe alpha-2 adrenergic receptor agonist is greater than about threehours, and if so, combining the alpha-2 adrenergic receptor agonist withone or more components or component precursors of the compositions orpolymeric drug delivery systems. The half-life may specifically beunderstood to be the intravitreal half-life after solution dosing of thealpha-2 adrenergic receptor agonist.

The present materials may also include salts of the anteriorly clearedalpha 2 adrenergic receptor agonist or other therapeutic agents whenappropriate. Pharmaceutically acceptable acid addition salts are thoseformed from acids which form non-toxic addition salts containingpharmaceutically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, sulfate, or bisulfate, phosphate or acidphosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate,citrate, gluconate, saccharate and p-toluene sulphonate salts.

As discussed herein, the present materials may be understood to beliquid-containing compositions. Thus, certain of the present materialsmay comprise a liquid carrier component associated with the therapeuticcomponent in the form of a composition suitable for administration to apatient by intravitreal administration and/or periocular administration.As used herein, periocular administration refers to delivery of thetherapeutic component to a retrobulbar region, a subconjunctival region,a subtenon region, a suprachoroidal region or space, and/or anintrascleral region or space. For example, an anteriorly cleared alpha 2adrenergic receptor agonist may be associated with water, saline,phosphate buffer, or other ophthalmically acceptable liquid carrier. Thepresent liquid-containing compositions are preferably in an injectableform. In other words, the compositions may be intraocularlyadministered, such as by intravitreal injection, using a syringe andneedle or other similar device (e.g., see U.S. Patent Publication No.2003/0060763), or the compositions can be periocularly administeredusing an injection device.

The therapeutic component of the present compositions may be present inan amount in the range of about 1% or less to about 5% or about 10% orabout 20% or about 30% or more (w/v or w/w) of the composition. Forintravitreally administered compositions, providing relatively highconcentrations or amounts of the therapeutic component in the presentcompositions may be beneficial in that reduced amounts of thecomposition may be required to be placed or injected into the posteriorsegment of the eye in order to provide the same amount or more of thetherapeutic component in the posterior segment of the eye relative toother compositions.

In certain embodiments, the material further comprises an excipientcomponent. The excipient component may be understood to includesolubilizing agents, viscosity inducing agents, buffer agents, tonicityagents, preservative agents, and the like.

In some embodiments of the present compositions, a solubilizing agentmay be a cyclodextrin. In other words, the present materials maycomprise a cyclodextrin component provided in an amount from about 0.1%(w/v) to about 5% (w/v) of the composition. In further embodiments, thecyclodextrin comprises up to about 10% (w/v) of certain cyclodextrins,as discussed herein. In further embodiments, the cyclodextrin comprisesup to about 60% (w/v) of certain cyclodextrins, as discussed herein. Theexcipient component of the present compositions may comprise one or moretypes of cyclodextrins or cyclodextrin derivatives, such asalpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, andderivatives thereof. As understood by persons of ordinary skill in theart, cyclodextrin derivatives refer to any substituted or otherwisemodified compound that has the characteristic chemical structure of acyclodextrin sufficiently to function as a cyclodextrin, for example, toenhance the solubility and/or stability of therapeutic agents and/orreduce unwanted side effects of the therapeutic agents and/or to forminclusive complexes with the therapeutic agents.

Viscosity inducing agents of the present materials, include withoutlimitation, polymers that are effective in stabilizing the therapeuticcomponent in the composition. The viscosity inducing component ispresent in an effective amount in increasing, advantageouslysubstantially increasing, the viscosity of the composition. Increasedviscosities of the present compositions may enhance the ability of thepresent compositions to maintain the therapeutic component, includingtherapeutic component particles, in substantially uniform suspension inthe compositions for prolonged periods of time, for example, for atleast about one week, without requiring resuspension processing. Therelatively high viscosity of the present compositions may also have anadditional benefit of at least assisting the compositions to have theability to have an increased amount or concentration of the therapeuticcomponent, as discussed elsewhere herein, for example, while maintainingsuch therapeutic component in substantially uniform suspension forprolonged periods of time.

Any suitable viscosity inducing component, for example, ophthalmicallyacceptable viscosity inducing component, may be employed in the presentcompositions. Many such viscosity inducing components have been proposedand/or used in ophthalmic compositions used on or in the eye. Theviscosity inducing component is present in an amount effective inproviding the desired viscosity to the composition. Advantageously, theviscosity inducing component is present in an amount in a range of about0.5% or about 1.0% to about 5% or about 10% or about 20% (w/v or w/w) ofthe composition. The specific amount of the viscosity inducing componentemployed depends upon a number of factors including, for example andwithout limitation, the specific viscosity inducing component beingemployed, the molecular weight of the viscosity inducing component beingemployed, the viscosity desired for the present composition beingproduced and/or used and the like factors.

The viscosity inducing component preferably comprises a polymericcomponent and/or at least one viscoelastic agent, such as thosematerials which are useful in ophthalmic surgical procedures. Examplesof useful viscosity inducing components include, but are not limited to,hyaluronic acid, carbomers, polyacrylic acid, cellulosic derivatives,polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides,polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivativesthereof and mixtures thereof.

The molecular weight of the presently useful viscosity inducingcomponents may be in a range of about 10,000 Daltons or less to about 2million Daltons or more. In one particularly useful embodiment, themolecular weight of the viscosity inducing component is in a range ofabout 100,000 Daltons or about 200,000 Daltons to about 1 millionDaltons or about 1.5 million Daltons. Again, the molecular weight of theviscosity inducing component useful in accordance with the presentinvention, may vary over a substantial range based on the type ofviscosity inducing component employed, and the desired final viscosityof the present composition in question, as well as, possibly one or moreother factors.

If desired, buffering agents may be provided in an amount effective tocontrol the pH of the composition. Tonicity agents may be provided in anamount effective to control the tonicity or osmolality of thecompositions. Certain of the present compositions include both a buffercomponent and a tonicity component, which may include one or more sugaralcohols, such as manitol, or salts, such as sodium chloride, asdiscussed herein. The buffer component and tonicity component may bechosen from those which are conventional and well known in theophthalmic art. Examples of such buffer components include, but are notlimited to, acetate buffers, citrate buffers, phosphate buffers, boratebuffers and the like and mixtures thereof. Phosphate buffers areparticularly useful. Useful tonicity components include, but are notlimited to, salts, particularly sodium chloride, potassium chloride, anyother suitable ophthalmically acceptably tonicity component and mixturesthereof.

The amount of buffer component employed preferably is sufficient tomaintain the pH of the composition in a range of about 6 to about 8,more preferably about 7 to about 7.5. The amount of tonicity componentemployed preferably is sufficient to provide an osmolality to thepresent compositions in a range of about 200 to about 400, morepreferably about 250 to about 350, mOsmol/kg respectively.Advantageously, the present compositions are substantially isotonic.

Preservative agents that may be used in the present materials includebenzyl alcohol, benzalkonium chloride, methyl and ethyl parabens,hexetidine, chlorite components, such as stabilized chlorine dioxide,metal chlorites and the like, other ophthalmically acceptablepreservatives and the like and mixtures thereof. The concentration ofthe preservative component, if any, in the present compositions is aconcentration effective to preserve the composition, and is often in arange of about 0.00001% to about 0.05% or about 0.1% (w/v) of thecomposition.

The present compositions can be produced using conventional techniquesroutinely known by persons of ordinary skill in the art. For example, atherapeutic component can be combined with a liquid carrier. Thecomposition can be sterilized. In certain embodiments, such aspreservative-free embodiments, the compositions can be sterilized andpackaged in single-dose amounts. The compositions may be prepackaged inintraocular dispensers which can be disposed of after a singleadministration of the unit dose of the compositions.

The present compositions can be prepared using suitableblending/processing techniques, for example, one or more conventionalblending techniques. The preparation processing should be chosen toprovide the present compositions in forms which are useful forintravitreal or periocular placement or injection into eyes of humans oranimals. In one useful embodiment a concentrated therapeutic componentdispersion is made by combining the therapeutic component with water,and the excipients (other than the viscosity inducing component) to beincluded in the final composition. The ingredients are mixed to dispersethe therapeutic component and then autoclaved. The viscosity inducingcomponent may be purchased sterile or sterilized by conventionalprocessing, for example, by filtering a dilute solution followed bylyophylization to yield a sterile powder. The sterile viscosity inducingcomponent is combined with water to make an aqueous concentrate. Theconcentrated therapeutic component dispersion is mixed and added as aslurry to the viscosity inducing component concentrate. Water is addedin a quantity sufficient (q.s.) to provide the desired composition andthe composition is mixed until homogenous.

In one embodiment, a sterile, viscous, suspension suitable foradministration is made using an anteriorly cleared alpha 2 adrenergicreceptor agonist. A process for producing such a composition maycomprise sterile suspension bulk compounding and asceptic filling.

Other embodiments of the present materials are in the form of apolymeric drug delivery system that is capable of providing sustaineddrug delivery for extended periods of time after a singleadministration. For example, the present drug delivery systems canrelease the anteriorly cleared alpha 2 adrenergic receptor agonist forat least about 1 month, or about 3 months, or about 6 months, or about 1year, or about 5 years or more. Thus, such embodiments of the presentmaterials may comprise a polymeric component associated with thetherapeutic component in the form of a polymeric drug delivery systemsuitable for administration to a patient by at least one of intravitrealadministration and periocular administration.

The polymeric drug delivery system may be in the form of biodegradablepolymeric implants, non-biodegradable polymeric implants, biodegradablepolymeric microparticles, and combinations thereof. Implants may be inthe form of rods, wafers, sheets, filaments, spheres, and the like.Particles are smaller than the implants disclosed herein, and may varyin shape. For example, certain embodiments of the present inventionutilize substantially spherical particles. These particles may beunderstood to be microspheres. Other embodiments may utilize randomlyconfigured particles, such as particles that have one or more flat orplanar surfaces. The drug delivery system may comprise a population ofsuch particles with a predetermined size distribution. For example, amajor portion of the population may comprise, particles having a desireddiameter measurement.

As discussed herein, the polymeric component of the present drugdelivery systems can comprise a polymer selected from the groupconsisting of biodegradable polymers, non-biodegradable polymers,biodegradable copolymers, non-biodegradable copolymers, and combinationsthereof. In certain embodiments, the polymeric component comprises apoly(lactide-co-glycolide) polymer (PLGA). In other embodiments, thepolymeric component comprises a polymer selected from the groupconsisting of poly-lactic acid (PLA), poly-glycolic acid (PGA),poly-lactide-co-glycolide (PLGA), polyesters, poly(ortho ester),poly(phosphazine), poly(phosphate ester), polycaprolactones, gelatin,collagen, derivatives thereof, and combinations thereof. The polymericcomponent may be associated with the therapeutic component to form animplant selected from the group consisting of solid implants, semisolidimplants, and viscoelastic implants.

The anteriorly cleared alpha 2 adrenergic receptor agonist may be in aparticulate or powder form and entrapped by a biodegradable polymermatrix. Usually, anteriorly cleared alpha 2 adrenergic receptor agonistparticles in intraocular implants will have an effective average sizeless than about 3000 nanometers. However, in other embodiments, theparticles may have an average maximum size greater than about 3000nanometers. In certain implants, the particles may have an effectiveaverage particle size about an order of magnitude smaller than 3000nanometers. For example, the particles may have an effective averageparticle size of less than about 500 nanometers. In additional implants,the particles may have an effective average particle size of less thanabout 400 nanometers, and in still further embodiments, a size less thanabout 200 nanometers. In addition, when such particles are combined witha polymeric component, the resulting polymeric intraocular particles maybe used to provide a desired therapeutic effect.

The anteriorly cleared alpha 2 adrenergic receptor agonist of thepresent systems is preferably from about 1% to 90% by weight of the drugdelivery system. More preferably, the anteriorly cleared alpha 2adrenergic receptor agonist is from about 20% to about 80% by weight ofthe system. In a preferred embodiment, the anteriorly cleared alpha 2adrenergic receptor agonist comprises about 40% by weight of the system(e.g., 30%-50%). In another embodiment, the anteriorly cleared alpha 2adrenergic receptor agonist comprises about 60% by weight of the system.

Suitable polymeric materials or compositions for use in the drugdelivery systems include those materials which are compatible, that isbiocompatible, with the eye so as to cause no substantial interferencewith the functioning or physiology of the eye. Such materials preferablyinclude polymers that are at least partially and more preferablysubstantially completely biodegradable or bioerodible.

In addition to the foregoing, examples of useful polymeric materialsinclude, without limitation, such materials derived from and/orincluding organic esters and organic ethers, which when degraded resultin physiologically acceptable degradation products, including themonomers. Also, polymeric materials derived from and/or including,anhydrides, amides, orthoesters and the like, by themselves or incombination with other monomers, may also find use. The polymericmaterials may be addition or condensation polymers, advantageouslycondensation polymers. The polymeric materials may be cross-linked ornon-cross-linked, for example not more than lightly cross-linked, suchas less than about 5%, or less than about 1% of the polymeric materialbeing cross-linked. For the most part, besides carbon and hydrogen, thepolymers will include at least one of oxygen and nitrogen,advantageously oxygen. The oxygen may be present as oxy, e.g. hydroxy orether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester,and the like. The nitrogen may be present as amide, cyano and amino. Thepolymers set forth in Heller, Biodegradable Polymers in Controlled DrugDelivery, In: CRC Critical Reviews in Therapeutic Drug Carrier Systems,Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which describesencapsulation for controlled drug delivery, may find use in the presentdrug delivery systems.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyesters,polyethers and combinations thereof which are biocompatible and may bebiodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present systems may include biocompatibility,compatibility with the therapeutic component, ease of use of the polymerin making the drug delivery systems of the present invention, ahalf-life in the physiological environment of at least about 6 hours,preferably greater than about one day, not significantly increasing theviscosity of the vitreous, and water insolubility.

The biodegradable polymeric materials which are included to form thematrix are desirably subject to enzymatic or hydrolytic instability.Water soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Also important to controlling the biodegradation of the polymer andhence the extended release profile of the drug delivery systems is therelative average molecular weight of the polymeric composition employedin the present systems. Different molecular weights of the same ordifferent polymeric compositions may be included in the systems tomodulate the release profile. In certain systems, the relative averagemolecular weight of the polymer will range from about 9 to about 64 kD,usually from about 10 to about 54 kD, and more usually from about 12 toabout 45 kD.

In some drug delivery systems, copolymers of glycolic acid and lacticacid are used, where the rate of biodegradation is controlled by theratio of glycolic acid to lactic acid. The most rapidly degradedcopolymer has roughly equal amounts of glycolic acid and lactic acid.Homopolymers, or copolymers having ratios other than equal, are moreresistant to degradation. The ratio of glycolic acid to lactic acid willalso affect the brittleness of the system, where a more flexible systemor implant is desirable for larger geometries. The % of polylactic acidin the polylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some systems,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the present systems may comprise amixture of two or more biodegradable polymers. For example, the systemmay comprise a mixture of a first biodegradable polymer and a differentsecond biodegradable polymer. One or more of the biodegradable polymersmay have terminal acid groups.

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or a combination of both. It may be understood thatthe polymeric component of the present systems is associated with thetherapeutic component so that the release of the therapeutic componentinto the eye is by one or more of diffusion, erosion, dissolution, andosmosis. As discussed herein, the matrix of an intraocular drug deliverysystem may release drug at a rate effective to sustain release of anamount of the anteriorly cleared alpha 2 adrenergic receptor agonist formore than one week after implantation into an eye. In certain systems,therapeutic amounts of the anteriorly cleared alpha 2 adrenergicreceptor agonist are released for more than about one month, and evenfor about twelve months or more. For example, the therapeutic componentcan be released into the eye for a time period from about ninety days toabout one year after the system is placed in the interior of an eye.

The release of the anteriorly cleared alpha 2 adrenergic receptoragonist from the drug delivery systems comprising a biodegradablepolymer matrix may include an initial burst of release followed by agradual increase in the amount of the anteriorly cleared alpha 2adrenergic receptor agonist released, or the release may include aninitial delay in release of the anteriorly cleared alpha 2 adrenergicreceptor agonist followed by an increase in release. When the system issubstantially completely degraded, the percent of the anteriorly clearedalpha 2 adrenergic receptor agonist that has been released is about onehundred.

It may be desirable to provide a relatively constant rate of release ofthe therapeutic agent from the drug delivery system over the life of thesystem. For example, it may be desirable for the anteriorly clearedalpha 2 adrenergic receptor agonist to be released in amounts from about0.01 μg to about 2 μg per day for the life of the system. However, therelease rate may change to either increase or decrease depending on theformulation of the biodegradable polymer matrix. In addition, therelease profile of the anteriorly cleared alpha 2 adrenergic receptoragonist may include one or more linear portions and/or one or morenon-linear portions. Preferably, the release rate is greater than zeroonce the system has begun to degrade or erode.

The drug delivery systems, such as the intraocular implants, may bemonolithic, i.e. having the active agent or agents homogenouslydistributed through the polymeric matrix, or encapsulated, where areservoir of active agent is encapsulated by the polymeric matrix. Dueto ease of manufacture, monolithic implants are usually preferred overencapsulated forms. However, the greater control afforded by theencapsulated, reservoir-type implant may be of benefit in somecircumstances, where the therapeutic level of the anteriorly clearedalpha 2 adrenergic receptor agonist falls within a narrow window. Inaddition, the therapeutic component, including the therapeutic agent(s)described herein, may be distributed in a non-homogenous pattern in thematrix. For example, the drug delivery system may include a portion thathas a greater concentration of the anteriorly cleared alpha 2 adrenergicreceptor agonist relative to a second portion of the system.

The polymeric implants disclosed herein may have a size of between about5 μm and about 2 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. The vitreous chamber in humans is able to accommodaterelatively large implants of varying geometries, having lengths of, forexample, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be acylindrical pellet with a length of about 7 mm to about 10 mm, and adiameter of about 0.75 mm to about 1.5 mm.

The implants may also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant. The total weight of the implant is usuallyabout 250-5000 μg, more preferably about 500-1000 μg. For example, animplant may be about 500 μg, or about 1000 μg. However, larger implantsmay also be formed and further processed before administration to aneye. In addition, larger implants may be desirable where relativelygreater amounts of the anteriorly cleared alpha 2 adrenergic receptoragonist are provided in the implant. For non-human individuals, thedimensions and total weight of the implant(s) may be larger or smaller,depending on the type of individual. For example, humans have a vitreousvolume of approximately 3.8 ml, compared with approximately 30 ml forhorses, and approximately 60-100 ml for elephants. An implant sized foruse in a human may be scaled up or down accordingly for other animals,for example, about 8 times larger for an implant for a horse, or about,for example, 26 times larger for an implant for an elephant.

Drug delivery systems can be prepared where the center may be of onematerial and the surface may have one or more layers of the same or adifferent composition, where the layers may be cross-linked, or of adifferent molecular weight, different density or porosity, or the like.For example, where it is desirable to quickly release an initial bolusof anteriorly cleared alpha 2 adrenergic receptor agonist, the centermay be a polylactate coated with a polylactate-polyglycolate copolymer,so as to enhance the rate of initial degradation. Alternatively, thecenter may be polyvinyl alcohol coated with polylactate, so that upondegradation of the polylactate exterior the center would dissolve and berapidly washed out of the eye.

The drug delivery systems may be of any geometry including fibers,sheets, films, microspheres, spheres, circular discs, plaques and thelike. The upper limit for the system size will be determined by factorssuch as toleration for the system, size limitations on insertion, easeof handling, etc. Where sheets or films are employed, the sheets orfilms will be in the range of at least about 0.5 mm×0.5 mm, usuallyabout 3-10 mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease ofhandling. Where fibers are employed, the fiber diameter will generallybe in the range of about 0.05 to 3 mm and the fiber length willgenerally be in the range of about 0.5-10 mm. Spheres may be in therange of about 0.5 μm to 4 mm in diameter, with comparable volumes forother shaped particles.

The size and form of the system can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. For example, larger implants will deliver aproportionately larger dose, but depending on the surface to mass ratio,may have a slower release rate. The particular size and geometry of thesystem are chosen to suit the site of implantation.

The proportions of therapeutic agent, polymer, and any other modifiersmay be empirically determined by formulating several implants, forexample, with varying proportions of such ingredients. A USP approvedmethod for dissolution or release test can be used to measure the rateof release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using theinfinite sink method, a weighed sample of the implant is added to ameasured volume of a solution containing 0.9% NaCl in water, where thesolution volume will be such that the drug concentration is afterrelease is less than 5% of saturation. The mixture is maintained at 37°C. and stirred slowly to maintain the implants in suspension. Theappearance of the dissolved drug as a function of time may be followedby various methods known in the art, such as spectrophotometrically,HPLC, mass spectroscopy, etc. until the absorbance becomes constant oruntil greater than 90% of the drug has been released.

In addition to the therapeutic component, and similar to thecompositions described herein, the polymeric drug delivery systemsdisclosed herein may include an excipient component. The excipientcomponent may be understood to include solubilizing agents, viscosityinducing agents, buffer agents, tonicity agents, preservative agents,and the like.

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the drug delivery systems. The amountof release modulator employed will be dependent on the desired releaseprofile, the activity of the modulator, and on the release profile ofthe therapeutic agent in the absence of modulator. Electrolytes such assodium chloride and potassium chloride may also be included in thesystems. Where the buffering agent or enhancer is hydrophilic, it mayalso act as a release accelerator. Hydrophilic additives act to increasethe release rates through faster dissolution of the material surroundingthe drug particles, which increases the surface area of the drugexposed, thereby increasing the rate of drug bioerosion. Similarly, ahydrophobic buffering agent or enhancer dissolve more slowly, slowingthe exposure of drug particles, and thereby slowing the rate of drugbioerosion.

Various techniques may be employed to produce the drug delivery systemsdescribed herein. Useful techniques include, but are not necessarilylimited to, solvent evaporation methods, phase separation methods,interfacial methods, molding methods, injection molding methods,extrusion methods, co-extrusion methods, carver press method, diecutting methods, heat compression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C.

In addition, the implant may be coextruded so that a coating is formedover a core region during the manufacture of the implant.

Compression methods may be used to make the drug delivery systems, andtypically yield elements with faster release rates than extrusionmethods. Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

In certain embodiments of the present invention, a method of producing asustained-release intraocular drug delivery system, comprises combiningan anteriorly cleared alpha 2 adrenergic receptor agonist and apolymeric material to form a drug delivery system suitable for placementin an eye of an individual. The resulting drug delivery system iseffective in releasing the anteriorly cleared alpha 2 adrenergicreceptor agonist into the eye for extended periods of time. The methodmay comprise a step of extruding a particulate mixture of the anteriorlycleared alpha 2 adrenergic receptor agonist and the polymeric materialto form an extruded composition, such as a filament, sheet, and thelike.

When polymeric particles are desired, the method may comprise formingthe extruded composition into a population of polymeric particles or apopulation of implants, as described herein. Such methods may includeone or more steps of cutting the extruded composition, milling theextruded composition, and the like.

As discussed herein, the polymeric material may comprise a biodegradablepolymer, a non-biodegradable polymer, or a combination thereof. Examplesof polymers include each and every one of the polymers and agentsidentified above.

Embodiments of the present invention also relate to compositionscomprising the present drug delivery systems. For example, and in oneembodiment, a composition may comprise the present drug delivery systemand an ophthalmically acceptable carrier component. Such a carriercomponent may be an aqueous composition, for example saline or aphosphate buffered liquid.

Another embodiment of the invention relates to anteriorly cleared alpha2 adrenergic receptor agonists. Such agonists have chemical or physicalstructures that are effective in providing an anterior clearance of theagonist from the eye to which they are administered. Such agonists canbe administered to the eye by intravitreal or periocular administration.Such agonists can be used in the manufacture of a medicament to treatone or more ocular conditions, such as glaucoma. In certain embodiments,the agonists can be used in a medicament to treat a condition affectingthe anterior segment of the eye and the posterior segment of the eye.

Another embodiment relates to a method of producing an ophthalmicallytherapeutic material which comprises an anteriorly cleared alpha 2adrenergic receptor agonist. In a broad aspect, the method comprises thesteps of selecting an alpha 2 adrenergic receptor agonist that has avitreous half-life greater than about 3 hours; and combining theselected alpha 2 adrenergic receptor agonist with a liquid carriercomponent or a polymeric component to form a material suitable foradministration to an eye. Or stated differently, a method of producingthe present materials may comprise a step of selecting alpha 2adrenergic receptor agonists having a high aqueous humor/vitreous humorconcentration ratio and long intravitreal half-lifes.

The method may further comprise one or more of the following steps,which will typically be used to select the anteriorly cleared alpha 2adrenergic receptor agonist: administering an alpha 2 adrenergicreceptor agonist to an eye of a subject and determining theconcentration of the alpha 2 adrenergic receptor agonist in at least oneof the vitreous humor and aqueous humor as a function of time; andadministering an alpha 2 adrenergic receptor agonist to an eye of asubject and determining at least one of the vitreous half-life andclearance of the alpha 2 adrenergic receptor agonist from the eye.

The material formed in the method may be a liquid-containingcomposition, a biodegradable polymeric implant, a non-biodegradablepolymeric implant, polymeric microparticles, or combinations thereof. Asdiscussed herein, the material may be in the form of solid implants,semisolid implants, and viscoelastic implants. In certain embodiments,the anteriorly cleared alpha 2 adrenergic receptor agonist is combinedwith a polymeric component to form a mixture, and the method furthercomprises extruding the mixture.

Additional embodiments of the present invention related to methods ofimproving or maintaining vision of an eye of a patient. In general, themethods comprise a step of administering the present ophthalmicallytherapeutic material to an eye of an individual in need thereof.Administration, such as intravitreal or periocular administration of thepresent materials can be effective in treating anterior ocularconditions, posterior ocular conditions, or combinations thereof. Forexample, certain of the present materials can be administered to apatient to provide neuroprotection to ocular neuronal cells and toreduce elevated intraocular pressure. The present materials may beparticularly useful in treating glaucoma. Administration of the presentmaterials are effective in delivering the alpha 2 adrenergic receptoragonist to one or more posterior structures of the eye including theuveal tract, the vitreous, the retina, the choroid, the retinal pigmentepithelium.

The present compositions and drug delivery systems can effectively treatanterior ocular conditions, such as conditions or diseases affecting theanterior segment of an eye (including the anterior chamber and posteriorchamber of the eye) when administered intraocularly into the posteriorsegment of an eye, or periocularly, as described above. In addition, thepresent compositions and drug delivery systems may also effectivelytreat posterior ocular conditions, such as conditions or diseasesaffecting the posterior segment of an eye (including the retina of theeye).

In additional embodiments, the present compositions and drug deliverysystems may be administered to a patient in combination with one or moretopical ophthalmic compositions. For example, the present compositionsand drug delivery systems may be administered in combination with acomposition effective in lowering intraocular pressure (IOP) of an eyeof a patient. The present combination therapies may enhance the anteriorclearance of the therapeutic agents of the present compositions and drugdelivery systems. For example, by lowering the IOP of a patient, forexample by about 5 mmHg, enhanced movement of the therapeutic agenttowards the anterior segment of the eye can be obtained. It has beenproposed that the movement of FITC-dextran from the vitreous into theaqueous was enhanced when IOP was lowered with a topical bunazosinsolution applied to rabbit eyes (Sugiura et al., “Effects of intraocularpressure change on movement of FITC-dextran across vitreous-aqueousinterface”, (1989), Jpn J. Opthalmol, 33(4):441-450).

Other combination therapies may include the administration of thepresent compositions and/or drug delivery systems in combination withsurgical procedures which attempt to decrease IOP. For example, thepresent compositions and/or drug delivery systems can be administered inpatients who have received or will be receiving trabecular meshworksurgery using a laser or mechanical surgical techniques.

Organic cations can be understood to be organic molecules having atransient or permanent positive net charge, for example at aphysiological pH. Examples of organic cations include anticholinergics,adrenergics, antineoplastics, sympathomimetics, antihistamines,xenobiotics, some vitamins, and a variety of endogenous amines, such ascholine, epinephrine, dopamine, and guanidine. Such organic cations canbe transported across barriers or membranes by organic cationtransporters. Inhibition, including competitive inhibition andnon-competitive inhibition, can reduce the transport of organic cationsusing organic cation transporters.

Thus, additional combination therapies may include administration of thepresent compositions and/or drug delivery systems in combination withadministration of an RPE organic cation transporter inhibitor. Forexample, administration of an RPE organic cation transporter inhibitormay decrease the posterior transport rate of the present alpha 2adrenergic receptor agonists and thereby cause an increase inintravitreal half-life of the alpha 2 adrenergic receptor agonists andan associated increase or enhancement in anterior clearance rate.Examples of suitable RPE organic cation transporter inhibitors includemetabolic inhibitors and organic cations. Examples of metabolicinhibitors include, without limitation,carbonylcyanide-p-(trifluoromethoxy)phenylhydrazone, 2,4-dinitrophenol,NaN₃, rotenone, and HgCl₂. Competitive inhibition can occur with organiccations. Examples of organic cations include, without limitation,quinacrine, pyrilamine, quinidine, valinomycin, diprivefrine, carbachol,diphenylhydramine, diltiazem, timolol, propanolol, and verapamil. Suchinhibitors are useful in inhibiting transport of verapamil in human RPEcell lines (Han et al., “Characterization of a Novel Cationic DrugTransporter in Human Retinal Pigment Epithelial Cells”, Journal ofPharmacology and Experimental Therapeutics, 296(2): 450-457, 2001).Other inhibitors include cimetidine, which is a high affinity inhibitorof organic cation transporter 2 (OCT2), and tyrosine, which is a highaffinity inhibitor of OCT1. In certain embodiments, the present alpha 2adrenergic receptor agonists can be administered to an eye of a patientin combination with an alpha 2 adrenergic receptor agonist that ispresent as a cation at physiological pHs. For example, the present alpha2 adrenergic receptor agonists can be administered in conjunction withbrimonidine. Such cationic alpha 2 adrenergic receptor agonists cancompetitively inhibit organic cation transport of the present alpha 2adrenergic receptor agonists.

The RPE organic cation transporter inhibitors can be administeredseparately from the present alpha 2 adrenergic receptor agonists, or canbe administered in combination with the present agonists. Thus, thecombination therapy may include administration of a single compositionor polymeric drug delivery system comprising the present alpha 2adrenergic receptor agonists and one or more RPE organic cationtransporter inhibitors.

When a syringe apparatus is used to administer the present materials,the apparatus can include an appropriately sized needle, for example, a27 gauge needle or a 30 gauge needle. Such apparatus can be effectivelyused to inject the materials into the posterior segment or a periocularregion of an eye of a human or animal. The needles may be sufficientlysmall to provide an opening that self seals after removal of the needle.

The present methods may comprise a single injection into the posteriorsegment of an eye or may involve repeated injections, for example overperiods of time ranging from about one week or about 1 month or about 3months to about 6 months or about 1 year or longer.

The present materials are preferably administered to patients in asterile form. For example, the present materials may be sterile whenstored. Any routine suitable method of sterilization may be employed tosterilize the materials. For example, the present materials may besterilized using radiation. Preferably, the sterilization method doesnot reduce the activity or biological or therapeutic activity of thetherapeutic agents of the present systems.

The materials can be sterilized by gamma irradiation. As an example, thedrug delivery systems can be sterilized by 2.5 to 4.0 mrad of gammairradiation. The drug delivery systems can be terminally sterilized intheir final primary packaging system including administration devicee.g. syringe applicator. Alternatively, the drug delivery systems can besterilized alone and then aseptically packaged into an applicatorsystem. In this case the applicator system can be sterilized by gammairradiation, ethylene oxide (ETO), heat or other means. The drugdelivery systems can be sterilized by gamma irradiation at lowtemperatures to improve stability or blanketed with argon, nitrogen orother means to remove oxygen. Beta irradiation or e-beam may also beused to sterilize the implants as well as UV irradiation. The dose ofirradiation from any source can be lowered depending on the initialbioburden of the drug delivery systems such that it may be much lessthan 2.5 to 4.0 mrad. The drug delivery systems may be manufacturedunder aseptic conditions from sterile starting components. The startingcomponents may be sterilized by heat, irradiation (gamma, beta, UV), ETOor sterile filtration. Semi-solid polymers or solutions of polymers maybe sterilized prior to drug delivery system fabrication and anteriorlycleared alpha 2 adrenergic receptor agonist incorporation by sterilefiltration of heat. The sterilized polymers can then be used toaseptically produce sterile drug delivery systems.

In addition to the anteriorly cleared alpha 2 adrenergic receptoragonist included in the present ophthalmically therapeutic materialsdisclosed hereinabove, the materials may also include one or moreadditional ophthalmically acceptable therapeutic agents. For example, anophthalmically therapeutic material may include one or moreantihistamines, one or more antibiotics, one or more beta blockers, oneor more steroids, one or more antineoplastic agents, one or moreimmunosuppressive agents, one or more antiviral agents, one or moreantioxidant agents, and mixtures thereof.

Examples of additional pharmacologic or therapeutic agents which mayfind use in the present materials, include, without limitation, thosedisclosed in U.S. Pat. Nos. 4,474,451, columns 4-6 and 4,327,725,columns 7-8.

Examples of antihistamines include, and are not limited to, loradatine,hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine,cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine,diphenylpyraline, phenindamine, azatadine, tripelennamine,dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazinedoxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, andderivatives thereof.

Examples of antibiotics include without limitation, cefazolin,cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan,cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin,cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone,cefadroxil, cephradine, cefuroxime, cyclosporine, ampicillin,amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin Vpotassium, piperacillin, oxacillin, bacampicillin, cloxacillin,ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin,erythromycin, tetracycline, doxycycline, minocycline, aztreonam,chloramphenicol, ciprofloxacin hydrochloride, clindamycin,metronidazole, gentamicin, lincomycin, tobramycin, vancomycin, polymyxinB sulfate, colistimethate, colistin, azithromycin, augmentin,sulfamethoxazole, trimethoprim, gatifloxacin, ofloxacin, and derivativesthereof.

Examples of beta blockers include acebutolol, atenolol, labetalol,metoprolol, propranolol, timolol, and derivatives thereof.

Examples of steroids include corticosteroids, such as cortisone,prednisolone, fluorometholone, dexamethasone, medrysone, loteprednol,fluazacort, hydrocortisone, prednisone, betamethasone, prednisone,methylprednisolone, riamcinolone hexacatonide, paramethasone acetate,diflorasone, fluocinonide, fluocinolone, triamcinolone, triamcinoloneacetonide, derivatives thereof, and mixtures thereof.

Examples of antineoplastic agents include adriamycin, cyclophosphamide,actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin,mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU),methyl-CCNU, cisplatin, etoposide, interferons, camptothecin andderivatives thereof, phenesterine, taxol and derivatives thereof,taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen,etoposide, piposulfan, cyclophosphamide, and flutamide, and derivativesthereof.

Examples of immunosuppresive agents include cyclosporine, azathioprine,tacrolimus, and derivatives thereof.

Examples of antiviral agents include interferon gamma, zidovudine,amantadine hydrochloride, ribavirin, acyclovir, valciclovir,dideoxycytidine, phosphonoformic acid, ganciclovir and derivativesthereof.

Examples of antioxidant agents include ascorbate, alpha-tocopherol,mannitol, reduced glutathione, various carotenoids, cysteine, uric acid,taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin,cryotpxanthin, astazanthin, lycopene, N-acetyl-cysteine, carnosine,gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid,citrate, Ginkgo Biloba extract, tea catechins, bilberry extract,vitamins E or esters of vitamin E, retinyl palmitate, and derivativesthereof.

Other therapeutic agents include squalamine, carbonic anhydraseinhibitors, alpha agonists, prostamides, prostaglandins, antiparasitics,antifungals, and derivatives thereof.

The present materials are configured to release an amount of theanteriorly cleared alpha 2 adrenergic receptor agonist effective totreat or reduce a symptom of an ocular condition, such as an ocularcondition such as glaucoma.

The materials disclosed herein may also be configured to deliveradditional therapeutic agents, as described above, which to preventdiseases or conditions, such as the following:

MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD),Choroidal Neovascularization, Diabetic Retinopathy, Acute MacularNeuroretinopathy, Central Serous Chorioretinopathy, Cystoid MacularEdema, Diabetic Macular Edema.

UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid PigmentEpitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy,Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), IntermediateUveitis (Pars Planitis), Multifocal Choroiditis, Multiple EvanescentWhite Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis,Serpignous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome,Vogt-Koyanagi-Harada Syndrome.

VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease, ParafovealTelangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle CellRetinopathy and other Hemoglobinopathies, Angioid Streaks, FamilialExudative Vitreoretinopathy.

TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal Disease,Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, HypoperfusionDuring Surgery, Radiation Retinopathy, Bone Marrow TransplantRetinopathy.

PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy andEpiretinal Membranes, Proliferative Diabetic Retinopathy, Retinopathy ofPrematurity (retrolental fibroplastic).

INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associated with HIV Infection, Uveitic Disease Associated withHIV Infection, Viral Retinitis, Acute Retinal Necrosis, ProgressiveOuter Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis.

GENETIC DISORDERS: Systemic Disorders with Accosiated RetinalDystrophies, Congenital Stationary Night Blindness, Cone Dystrophies,Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the RetinalPigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy,Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy,pseudoxanthoma elasticum, Osler Weber syndrome.

RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant RetinalTear.

TUMORS: Retinal Disease Associated with Tumors, Solid Tumors, TumorMetastasis, Benign Tumors, for example, hemangiomas, neurofibromas,trachomas, and pyogenic granulomas, Congenital Hypertrophy of the RPE,Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma,Choroidal Metastasis, Combined Hamartoma of the Retina and RetinalPigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of theOcular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior MultifocalPlacoid Pigment Epitheliopathy, Myopic Retinal Degeneration, AcuteRetinal Pigment Epithelitis, Ocular inflammatory and immune disorders,ocular vascular malfunctions, Corneal Graft Rejection, NeovascularGlaucoma and the like.

In another aspect of the invention, kits for treating an ocularcondition of the eye are provided, comprising: a) a container, such as asyringe or other applicator, comprising an anteriorly cleared alpha 2adrenergic receptor agonist as herein described; and b) instructions foruse. Instructions may include steps of how to handle the material, howto insert the material into an ocular region, and what to expect fromusing the material. The container may contain a single dose of theanteriorly cleared alpha 2 adrenergic receptor agonist.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred drug delivery systems, methods of makingsuch systems, and methods to treat conditions within the scope of thepresent invention. The following examples are not intended to limit thescope of the invention.

Example 1 Intravitreal Clearance of Brimonidine

Intravitreal clearance of brimonidine was examined in albino rabbits.Rabbits were dosed bilaterally via a 50 microliter intravitrealinjection of a solution containing 928 nanograms of brimonidine.Vitreous humor samples were collected at different time points and thebrimonidine concentration in the vitreous humor was determined.

As shown in FIG. 1, the vitreal concentration of brimonidine declinedexponentially from 608±116 ng/mL at 0.5 hours post dose to 9.68±6.48ng/mL at 10 hours post dose. The estimated vitreous half-life (t_(1/2))of brimonidine was determined to be 1.45 hours. The vitreal clearancerate was estimated to be 0.487 mL/hour.

Based on these results, it was concluded that brimonidine is eliminatedfrom the vitreous by a trans-retinal route. These results demonstratethat hydrophilic to moderately lipophilic alpha 2 adrenergic receptoragonists having a trans-retinal route of clearance from the posteriorsegment of the eye, cannot be effectively delivered to the anteriorand/or posterior chambers of the eye via intravitreal administration.

Example 2 Pharmacokinetic Properties of Brimonidine IntravitrealImplants

Biodegradable polymeric implants containing brimonidine were prepared inaccordance with the methods described herein. The implants were madefrom polylactic acid (PLA) and included 200 micrograms of brimonidine.These brimonidine implants were administered to the vitreous of rabbiteyes. Vitreous humor and aqueous humor samples were obtained at varioustime points, and the amount of brimonidine was determined in thesamples, as shown in Table 1 below TABLE 1 Brimonidine ConcentrationAqueous Iris-ciliary Vitreous Humor body Lens Retina humor Day (ng/mL)(ng/g) (ng/g) (ng/g) (ng/mL) 8 NC 942 (3010)^(d) 45.1 ± 13.4 3630 ± 47.2± 2111 13.1 31 NC 25.9 ± 9.11 17.0 ± 3.92 35.3 ± 9.35 ± 15.5 6.25^(b) 58NC 69.4 ± 55.3  17.9 ± 12.5^(b) 122 ± 5.6 ± 57.3^(a) 3.24^(b) 91 NC 42.9 ± 18.7^(c) 50.1 ± 14.8 488 ± 59.3 ± 471^(b) 43.2 136 NC  107 ±41.5  16.2 ± 12.3^(a) 22.6 ± NC 5.9 184 NC NC  1.18 ± 0.71^(b) 59.8 ± NC35.0^(b)

In Table 1, NC means “not calculable” because greater than 50% ofconcentrations contributing to the mean were BLQ (below the limit ofquantitation). The data are expressed as the mean ±SEM (N=4 eyes and N=2plasma per sampling time). In addition, the letters a, b, c, and d aredefined as follows:

a N=4. One sample was BLQ (included in the mean calculation as 0).

b N=4. Two samples were BLQ (included in the mean calculation as 0).

c N=3. One sample was not detectable (ND).

d N=2. Two samples were above the limit of quantitation (estimated meanvalue in parentheses).

The EC₅₀ for brimonidine to activate the alpha 2 adrenergic receptor inisolated assay systems is about 2 nM. Based on doubling this as a targetconcentration (C_(ss)) and the vitreal clearance (Cl) a constantdelivery of 2.5 μg of brimonidine at 0.57 ng/hour (R_(o)) is desirablefor intravitreal implant devices to maintain the desired steady statedrug level for, a duration of six months using the following equation:R_(o)=C_(ss)*Cl.

Unexpectedly, as shown in Table 1, when the brimonidine implants wereimplanted in the vitreous, the implants released brimonidine to providehigh vitreous and retinal concentrations of brimonidine that weremaintained over a long period of time but only provided low orundetectable amounts of brimonidine in the aqueous humor. Thus, thebrimonidine implants resulted in therapeutic levels of brimonidine atthe retina for neuroprotection, but not in the anterior chamber. Thus,it was concluded that brimonidine when administered intravitreally canprovide a neuroprotective effect, but may not provide a reduction inintraocular pressure associated with effects in the anterior segment ofthe eye.

Example 3 Pharmacokinetic Properties of Brimonidine SubconjunctivalAdministered to an Eye

Brimonidine was administered to the subconjunctiva of New Zealand Whiterabbits by implantation of a polylactic acid (PLA) wafer containing 250μg of brimonidine, a poly-ortho-ester (POE) rod containing 200 μg ofbrimonidine, or a single 100 μL injection containing 20 μg or 200 μg ofbrimonidine PLA microspheres. A 100 μL injection of 10 mg/mL ofmicrospheres (20 μg brimonidine) contained 98% (w/w) of PLA polymerhaving an inherent viscosity of 0.6 dl/g (i.e., 980 μg of PLA) and 2%(w/w) of brimonidine free base (i.e., 20 μg). A less than or equal to100 μL or 200 μL injection of 100 mg/mL or 200 mg/mL microspheres,respectively (200 μg brimonidine) contained 98% (w/w) of PLA polymerhaving an inherent viscosity of 0.6 dL/g (i.e. 9.8 mg of PLA), and 2%(w/w) of brimonidine free base (i.e., 200 μg). A 1 mg waver containing250 μg brimonidine contained 75% (w/w) PLA (R206) polymer (750 μg), and25% (w/w) of brimonidine tartrate (250 μg). A 1 mg rod containing 250 μgof brimonidine contained 80% (w/w) of APF 255 POE (APF94) polymer (800μg) and 20% (w/w) of brimonidine (200 μg). A 1 mg rod containing 200 μgof brimonidine contained 80% (w/w) of APF 260 POE (APF99) polymer (800μg) and 20% (w/w) of brimonidine (200 μg). A 1 mg rod containing 200 μgof brimonidine contained 80% (w/w) of APF 423 POE (APF162) polymer (800μg) and 20% (w/w) of brimonidine (200 μg).

Thirty groups of rabbits (2 rabbits per group) were used. The groupswere divided into 6 sections of 5 groups. One section received 10 mg/mLof microspheres containing 20 μg of brimonidine, one section received100 mg/mL of microspheres containing 200 μg of brimonidine, one sectionreceived 1 mg POE-AP94 implants containing 200 μg of brimonidine, onesection received 1 mg POE-AP99 implants containing 200 μg ofbrimonidine, one section received 1 mg POE-AP162 implants containing 200μg of brimonidine, and one section received 1 mg PLA wafers containing250 μg of brimonidine. In each section, one group underwent ophthalmicobservation at 5 days after dosing (DAD) and were euthanized at 8 DAD,one group underwent ophthalmic observation at 5 and 29 DAD and wereeuthanized at 31 DAD, one group underwent ophthalmic observation at 5,29, and 54 DAD and were euthanized at 60 DAD, and two groups underwentophthalmic observation at 5, 29, 54, and 86 DAD and were euthanized at93 DAD. The drug delivery systems were formulated to provide a 10-20 nM(3-6 ng/mL) brimonidine target concentration since the at least 2 nM ofbrimonidine are required to provide optic neuroprotection.

The dose of brimonidine was based on a vitreal clearance rate of 0.487ml/day and a target therapeutic concentration for brimonidine. Based onthe relationship C_(ss)=R_(o)/Cl, where R_(o)=delivery rate,C_(ss)=steady-state concentration, and Cl=vitreal clearance, the releaserate over a 3 month period of time was calculated to be about 1.46-2.92ng/day. The 10 mg/mL and 100 mg/mL microspheres provided release ratesof 1.4 and 14 μg/day for 60 days. The APF255, APF260, and APF423provided release rates of about 2.2, 2.6, and 2.5 μg/day, respectively.The PLA wafer provided a release rate of about 5 μg/day over 30 days and1.25 μg/day out to 90 days. A single implant was sufficient, andconventional methods were used to determine intraocular and systemicpharmacokinetics.

Eyes were prepared for surgery by topical application of two drops of 1%tropicamide and two drops of phenylephrine hydrochloride 2.5%. Betadinewas applied and washed from the eyes, and 1-2 drops of 0.5% proparacainehydrochloride were delivered to each eye. After a 3 mm conjunctivalincision was made extending from the limbus and lateral to the dorsalrectus muscle, a single subconjunctival injection or implantation of abrimonidine drug delivery system was made. Rods and wafers wereadministered using forceps. Conjunctivae were sutured closed andreceived a ocular lubricant. Subconjunctival injections were performedby elevating the bulbar conjunctiva in the dorsotemporal quadrant usingforceps. An injection was made into the subconjunctival space.

Gross ocular examinations were performed once weekly and during thefirst week, more thorough ophthalmic examinations (slit lamp andindirect opthalmoscopy) were performed instead. The examinationsincluded observations of the eyelids, conjunctiva, cornea, anteriorchamber, iris, lens, vitreous, and retina. Intraocular pressure (IOP)was recorded at 8 am, 12 noon and 4 pm using a Medtronic Solan, Model 30classic pneumatonometer on conditioned rabbits. Tear tissue, aqueoushumor tissue, and remaining tissues were collected and stored.

Based on gross ocular examinations, no conjunctival congestion,swelling, or discharge was observed.

Based on slit lamp and indirect opthalmoscopy, an insignificant numberof eyes exhibited conjunctival congestion. A minor number of eyes wereobserved to have cataracts that were concluded to not be drug-related.Conjunctival pigmentation was observed in some eyes, and was notconsidered to be of toxicological significance. Similarly, some eyesexhibited increased vascularization which was not considered to betoxicocologically significant.

At day 14, the mean IOP fore eyes treated with APF 423 POE implants (200μg brimonidine) were significantly higher than the mean IOP at baselineat 8:00 am. Higher IOP was also observed at days 7, 14, 56, and 89/90 at4:00 pm for eyes treated with APF 423.

At day 30, mean IOP for eyes treated with APF 255 POE implants (200 μgbrimonidine) was significantly lower than the mean IOP at baseline forplacebo treated eyes at 8:00 am and noon. At day 56, mean IOP for eyestreated with APF 255 was significantly lower than the mean IOP for baseat 8:00 am and noon.

At day 30, mean IOP for eyes treated with APF 260 POE implants (200 μgbrimonidine) was significantly lower than the mean IOP for baseline at8:00 am and lower than the mean IOP for baseline and placebo-treatedeyes at noon.

At day 56, the mean IOP at 8:00 am, noon, and 4:00 pm for eyes treatedwith PLGA1206_(—)01 microspheres (20 μg brimonidine) was significantlylower than the mean IOP for baseline.

Following a single bilateral subconjunctival implantation of APF 255POE, APF 260 POE or APF 423 POE rod, brimonidine was detected at belowthe limit of quantitation levels in all ocular tissues at every timepoint up to day 91 post implant, except for the lens tissue at day 8with the APF 255 POE implant. Following a single subconjunctivalimplantation of BF9 waver, brimonidine was detected at BLQ levels in allocular tissues. Following a single subconjunctival injection of 100 μLmicrospheres, brimonidine was detected at BLQ levels in all tissues atall time points up to day 91 post implant, except for the iris-ciliarybody at day 8 and day 33, and the lens at day 8 and day 33.

Plasma brimonidine concentrations were below the lower limit ofquantitation in all samples. The concentrations of brimonidine observedare described in Tables 2-7 below TABLE 2 brimonidine concentrationfollowing subconjunctival injection of 100 μL microspheres containing 20μg brimonidine Brimonidine Concentration Aqueous Iris-ciliary VitreousHumor body Lens Retina Humor Plasma Day (ng/mL) (ng/g) (ng/g) (ng/g)(ng/mL) (ng/mL 8 NC 4.36 ± 3.04^(a) NC NC NC NC 33 NC 18.1 ± 3.0^(a) 1.40 ± NC NC 0.040^(c) 0.73^(b) (BLQ, 0.079) 57 NC NC NC NC NC NC 91 NCNC NC NC NC NC

In Table 2, NC=not calculable, a means N=4 and one sample is BLQ, bmeans N=4 and two samples are BLQ, and c means N=2, and one sample isBLQ. TABLE 3 brimonidine concentrations following subconjunctivalinjection of 100 μL microspheres containing 200 μg brimonidineBrimonidine Concentration Aqueous Iris-ciliary Vitreous Humor body LensRetina Humor Plasma Day (ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC26.9 ± 10.8 10.4 ± NC NC NC 9.7^(a) 33 NC NC 0.703 ± NC NC NC 0.352^(b)57 NC NC NC NC NC NC 91 NC NC NC NC NC NC

In Table 3, NC=not calculable, a means N=4 and one sample is BLQ, and bmeans N=4 and two samples are BLQ. TABLE 4 brimonidine concentrationsfollowing subconjunctival implantation of APF 255 POE containing 200 μgbrimonidine Brimonidine Concentration Aqueous Iris-ciliary VitreousHumor body Lens Retina Humor Plasma Day (ng/mL) (ng/g) (ng/g) (ng/g)(ng/mL) (ng/mL 8 NC NC 0.463 ± NC NC NC 0.463^(a) 33 NC NC NC NC NC NC57 NC NC NC NC NC NC 91 NC NC NC NC NC NC

In Table 4, NC=not calculable, and a means N=4 and two samples are BLQ.TABLE 5 brimonidine concentrations following subconjunctivalimplantation of APF 260 POE containing 200 μg brimonidine BrimonidineConcentration Aqueous Iris-ciliary Vitreous Humor body Lens Retina HumorPlasma Day (ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC NC NC NC NCNC 33 NC NC NC NC NC 0.064^(a) (BLQ, 0.127) 57 NC NC NC NC NC NC 91 NCNC NC NC NC 0.59^(a) (BLQ, 1.17

In Table 5, NC=not calculable, and a means N=2 and one sample is BLQ.TABLE 6 brimonidine concentrations following subconjunctivalimplantation of APF 423 POE implant containing 200 μg brimonidineBrimonidine Concentration Aqueous Iris-ciliary Vitreous Humor body LensRetina Humor Plasma Day (ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NCNC NC NC NC NC 33 NC NC NC NC NC NC 57 NC NC NC NC NC 0.267^(a) (0.267,BLQ) 91 NC NC NC NC NC 0.084^(a) (BLQ, 0.167)

In Table 6, NC not calculable, and a means N=2 and one sample is BLQ.TABLE 7 brimonidine concentrations following subconjunctivalimplantation of a wafer containing 250 μg brimonidine BrimonidineConcentration Aqueous Iris-ciliary Vitreous Humor body Lens Retina HumorPlasma Day (ng/mL) (ng/g) (ng/g) (ng/g) (ng/mL) (ng/mL 8 NC NC NC NC NCNC 33 NC NC NC NC NC NC 57 NC NC NC NC NC NC 91 NC NC NC NC NC 0.032^(a)(BLQ, 0.063)

In Table 7, NC=not calculable, and a means N=2 and one sample is BLQ.

In the above, the samples were quantified using LC-MS/MS methods withquantitation limits of 10 ng/mL for aqueous and vitreous humor samples,0.05 ng/mL for plasma samples, 0.5 ng for iris-ciliary body samples,lens samples, and retina samples.

In summary, subconjunctival administration of polymeric drug deliverysystems containing 20-250 μg of brimonidine was unable to deliversufficient amounts of brimonidine to the aqueous humor to reduce IOP.Using these drug delivery systems and methods of delivery, therapeuticintraocular concentrations of brimonidine were not observed.

Example 4 Manufacture and Testing of Drug Delivery Systems Containing anAnteriorly Cleared Alpha 2 Adrenergic Receptor Agonist and aBiodegradable Polymer Matrix

Biodegradable drug delivery systems are made by combining a anteriorlycleared alpha 2 adrenergic receptor agonist with a biodegradable polymercomposition in a stainless steel mortar. The combination is mixed via aTurbula shaker set at 96 RPM for 15 minutes. The powder blend is scrapedoff the wall of the mortar and then remixed for an additional 15minutes. The mixed powder blend is heated to a semi-molten state atspecified temperature for a total of 30 minutes, forming a polymer/drugmelt.

Rods are manufactured by pelletizing the polymer/drug melt using a 9gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into thebarrel and extruding the material at the specified core extrusiontemperature into filaments. The filaments are then cut into about 1 mgsize implants or drug delivery systems. The rods have dimensions ofabout 2 mm long×0.72 mm diameter. The rod implants weigh between about900 μg and 1100 μg.

Wafers are formed by flattening the polymer melt with a Carver press ata specified temperature and cutting the flattened material into wafers,each weighing about 1 mg. The wafers have a diameter of about 2.5 mm anda thickness of about 0.13 mm. The wafer implants weigh between about 900μg and 1100 μg.

In-vitro release testing can be performed on each lot of implant (rod orwafer). Each implant may be placed into a 24 mL screw cap vial with 10mL of Phosphate Buffered Saline solution at 37° C. and 1 mL aliquots areremoved and replaced with equal volume of fresh medium on day 1, 4, 7,14, 28, and every two weeks thereafter.

Drug assays may be performed by HPLC, which consists of a Waters 2690Separation Module (or 2696), and a Waters 2996 Photodiode ArrayDetector. An Ultrasphere, C-18 (2), 5 μm; 4.6×150 mm column heated at30° C. can be used for separation and the detector can be set at 264 nm.The mobile phase can be (10:90) MeOH-buffered mobile phase with a flowrate of 1 mL/min and a total run time of 12 min per sample. The bufferedmobile phase may comprise (68:0.75:0.25:31) 13 mM 1-Heptane SulfonicAcid, sodium salt-glacial acetic acid-triethylamine-Methanol. Therelease rates can be determined by calculating the amount of drug beingreleased in a given volume of medium over time in μg/day.

The polymers chosen for the implants can be obtained from BoehringerIngelheim or Purac America, for example. Examples of polymers include:RG502, RG752, R202H, R203 and R206, and Purac PDLG (50/50). RG502 is(50:50) poly(D,L-lactide-co-glycolide), RG752 is (75:25)poly(D,L-lactide-co-glycolide), R202H is 100% poly(D, L-lactide) withacid end group or terminal acid groups, R203 and R206 are both 100%poly(D, L-lactide). Purac PDLG (50/50) is (50:50)poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502, RG752,R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3, 1.0, and 0.2dL/g, respectively. The average molecular weight of RG502, RG752, R202H,R203, R206, and Purac PDLG are, 11700, 11200, 6500, 14000, 63300, and9700 daltons, respectively.

Example 5 Treatment of Glaucoma with an Anteriorly Cleared Alpha 2Adrenergic Receptor Agonist Implant

A 58 year old man diagnosed with glaucoma is treated by administrationof a biodegradable drug delivery system administered to each eye of thepatient. A 1 mg intravitreal implant containing about 500 μg of PLGA andabout 500 μg of an anteriorly cleared alpha 2 adrenergic receptoragonist is placed in his left eye at a location that does not interferewith the man's vision. A similar implant is administeredsubconjunctivally to the patient's right eye. A more rapid reduction inintraocular pressure in the right eye appears to be due to the locationof the implant. After about 3 months from the surgery, the man'sintraocular pressure remains steady at acceptable levels, anddegeneration of the optic nerve appears to be reduced.

Example 6 Treatment of Glaucoma with an Anteriorly Cleared Alpha 2Adrenergic Receptor Agonist Composition

A 62 year old woman with glaucoma is treated with an intravitrealinjection of a solution containing about 20 μg of an anteriorly clearedalpha 2 adrenergic receptor agonist. The patient exhibits an acceptablereduction in elevated intraocular pressure and a decrease in nervedegeneration. The patient reports an overall improvement in quality oflife.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1-24. (canceled)
 25. A method of improving or maintaining vision of aneye of a patient, comprising the step of administering an ophthalmicallytherapeutic material to an eye of an individual, wherein saidophthalmically therapeutic material comprises: a therapeutic componentcomprising a therapeutically effective amount of an alpha 2 adrenergicreceptor agonist having a structure effective in providing eliminationof the agonist from the anterior chamber of an eye to which the agonistis administered.
 26. The method of claim 25, wherein the method iseffective to treat an ocular condition selected from the groupconsisting of anterior ocular condition, posterior ocular conditions,and combinations thereof.
 27. The method of claim 25, wherein the methodis effective to provide neuroprotection to ocular neuronal cells and toreduce elevated intraocular pressure.
 28. The method of claim 25,wherein the method is effective in treating glaucoma.
 29. The method ofclaim 25, wherein the material is administered by a step selected fromthe group consisting of intraocular administration, periocularadministration, and combinations thereof.
 30. The method of claim 25,wherein the material is administered by intravitreal injection of thematerial into the eye.
 31. The method of claim 25, wherein theadministering comprises subconjunctival administration or periocularadministration to deliver the alpha 2 adrenergic receptor agonist to aposterior structure of the eye selected from the group consisting of:the uveal tract, the vitreous, the retina, the choroid, the retinalpigment epithelium, and combinations thereof.
 32. The method of claim25, wherein the administering comprises administering the material to alocation in the eye selected from the group consisting of the anteriorchamber, the posterior chamber, and combinations thereof.
 33. The methodof claim 25, wherein the administering comprises using a syringe or atrocar to administer the material to the eye.
 34. The method of claim25, wherein said ophthalmically therapeutic material further comprises apolymeric component associated with a therapeutic component in the formof a polymeric drug delivery system suitable for administration to apatient by at least one of intravitreal administration and periocularadministration.
 35. The method of claim 34, wherein the polymeric drugdelivery system is selected from the group consisting of biodegradablepolymeric implants, non-biodegradable polymeric implants, biodegradablepolymeric microparticles, and combinations thereof.
 36. The method ofclaim 34, wherein the polymeric component comprises apoly(lactide-co-glycolide) polymer.
 37. The method of claim 34, whereinthe polymeric component comprises a polymer selected from the groupconsisting of poly-lactic acid (PLA), poly-glycolic acid (PGA),poly-lactide-co-glycolide (PLGA), polyesters, poly(ortho ester),poly(phosphazine), poly(phosphate ester), polycaprolactones, gelatin,collagen, derivatives thereof, and combinations thereof.
 38. The methodof claim 34, wherein the therapeutic component and the polymericcomponent are associated in the form of an implant selected from thegroup consisting of solid implants, semisolid implants, and viscoelasticimplants.
 39. The method of claim 25, wherein the alpha 2 adrenergicreceptor agonist is provided in an amount to provide a therapeuticeffect selected from the group consisting of neuroprotection, reductionin intraocular pressure, and combinations thereof.
 40. The method ofclaim 25, wherein the alpha 2 adrenergic receptor agonist is coupled toa polyethylene glycol.
 41. The method of claim 25, wherein the alpha 2adrenergic receptor agonist has a structure effective in providingsubstantially equal elimination rates from the anterior chamber of theeye and the posterior segment of the eye.
 42. The method of claim 25,wherein the alpha 2 adrenergic receptor agonist has a structureeffective in providing a greater enhanced anterior elimination raterelative to a posterior elimination rate.